DESCRIPTION: (Applicant's Abstract) The abuse of amphetamine-like psychostimulants is a medical and social problem throughout the world. The rewarding properties of amphetamine-like stimulants are linked to the capacity of these drugs to increase extracellular concentrations of dopamine in the forebrain, notably in the nucleus accumbens. Despite the advances in our understanding of the cellular and molecular actions of psychostimulants, effective pharmacological treatments for amphetamine and cocaine addition remain elusive. However, several preclinical studies report that calcium channel antagonists influence psychostimulant self-administration and conditioned place preference in rodents in a manner similar to dopamine antagonists. These results suggest that drugs acting on calcium conductances and associated transduction pathways may be potentially effective therapeutic agents for treating psychostimulant abuse. Interestingly, repeated injections of amphetamine-like psychostimulants results in an enhancement in the ability of these drugs to increase extracellular dopamine in the nucleus accumbens, and calcium appears to play an important role in this process. The studies outlined in this proposal will: i)identify the mechanisms that underlie the influence of calcium and calcium-stimulated kinases on the enhanced increase in dopamine in the nucleus accumbens of cocaine-pretreated rats and ii) assess the behavioral relevance of these changes in dopamine neuronal function. Since the enhanced increase in dopamine in the nucleus accumbens is observed in both rats that self-administer or receive daily systemic injections of cocaine, the identification of novel mechanisms underlying this neurochemical adaptation to repeated cocaine may have direct clinical significance. Thus, by outlining the role of calcium in the cellular and molecular effects of psychostimulant drugs, the results of the experiments outlined in this proposal could guide the development of novel treatment strategies for amphetamine and cocaine addiction.